Stabilized particle dispersions containing nanoparticles

ABSTRACT

In one aspect, the invention provides a stable dispersion comprising a continuous phase comprising a continuous liquid phase and a plurality of organic nanoparticles; and a dispersed phase comprising particles dispersed in the continuous phase.

BACKGROUND

Traditional dispersions are made up of two phases: a dispersed phase anda continuous phase. The most common dispersions consist of dispersedparticles and a liquid continuous phase. If the formed dispersion is notstabilized, the dispersed particles tend to flocculate or agglomerateand the two phases will separate. Typically, dispersants are used toprevent the two phases from completely separating. Dispersants stabilizedispersions after being adsorbed onto the dispersed particles.Increasing the viscosity of the continuous phase may also preventcomplete phase separation of dispersions.

SUMMARY

In one aspect, the invention provides a stable dispersion comprising acontinuous phase comprising a continuous liquid phase and organicnanoparticles; and a dispersed phase comprising particles dispersed inthe continuous phase.

In another aspect, the invention provides a method of stabilizing adispersion comprising adding an effective amount of organicnanoparticles to a dispersion comprising a dispersed solid phase and aliquid continuous phase.

In another aspect, the invention provides a method for treating a mammalcomprising administering a therapeutically effective amount of amedicament dispersion according to the invention to the mammal byadministration methods selected from the group consisting of orally,injection, topically, through its nasal passage, by inhalation, andcombinations thereof.

In another aspect, the invention provides a dispersion kit comprising adispersed phase component to be dispersed in a continuous phase, andorganic nanoparticles.

DETAILED DESCRIPTION

The dispersions of the invention are stable dispersions that remaindispersed over a useful time period without substantial agitation of thedispersion or which are easily redispersed with minimal energy input.The dispersions comprising dispersed particles and a continuous phaseare rendered stable by incorporation of an effective amount of organicnanoparticles into the continuous phase. An “effective amount” oforganic nanoparticles is an amount that minimizes the aggregation of thedispersed particles and forms stable dispersions that remain dispersedover a useful time period without substantial agitation of thedispersion or which are easily redispersed with minimal energy input.Without wishing to be bound by any theory, the nanoparticles arebelieved to sterically inhibit the aggregation of the dispersedparticles and not through particle charge. The nanoparticles used in thedispersions of the invention appear to be soluble in the continuousphase of the dispersion and do not precipitate, flocculate, etc., in thedispersions of the invention. In addition, the nanoparticles do notsubstantially associate with the surface of the dispersed particles andmay be effective suspension aids at low concentrations as compared withconventional suspension aids. The stable dispersions of the inventionmay contain less than 0.001 weight percent of surfactant, surface-activeagents, traditional emulsifiers, detergents, and/or protective colloids.

As used herein, “dispersion” means a solid distributed throughout aliquid continuous phase which does not separate over a useful timeperiod.

As used herein, “separate” means that the solid particles in a liquiddispersion gradually settle or cream, forming distinct layers with verydifferent concentrations of the solid particles and continuous liquidphase.

As used herein, “dispersion stability” is a description of the tendencyof a dispersion to separate. For a dispersion with good dispersionstability, the particles remain approximately homogeneously distributedwithin the continuous phase. For a dispersion with poor dispersionstability, the particles do not remain approximately homogeneouslydistributed within the continuous phase and may separate.

As used herein, an “excipient” refers broadly to any inert additiveother than the primary active medicament moiety used to improve someaspect of the aerosol dispersion formulation.

As used herein, “nanoparticles” means organic particles or moleculesthat appear to be soluble in the continuous phase wherein each organicparticle has nanoscale dimensions in the continuous phase and thatoccupies or provides a zone of steric exclusion of less than 100nanometers, within the continuous phase.

Stabilized dispersions of the invention include surface-modified organicnanoparticles, and/or steric organic molecules having un-modifiedsurfaces (nanoparticles). “Steric organic molecules” means singlemolecules (for example, polymers) that have an exclusion volumedescribable in nanometer diameter dimensions and comprised ofcovalently-bound organic units. “Steric organic molecules” do notinclude linear polymers that are soluble in the continuous phase. In oneembodiment, they are substantially composed of the same moieties on thesurface as are present in the inner portion or core of the nanoparticle.The nanoparticles are desirably individual, unassociated (i.e.,non-aggregated) nanoparticles dispersed throughout the continuous phaseand desirably do not irreversibly associate with each other and do notassociate with the dispersed medicament. The term “associate with” or“associating with” includes, for example, covalent bonding, hydrogenbonding, electrostatic attraction, London forces, and hydrophobicinteractions.

The nanoparticles are selected such that the composition formedtherewith is free from a degree of particle agglomeration or aggregationthat would interfere with the desired properties of the composition. Thesurface-modified organic nanoparticles have surface groups that modifythe “solubility” or “wettability” characteristics of the nanoparticles.The surface groups are selected to render the particle compatible withthe continuous phase including components of the continuous phase. Theun-modified nanoparticles are compatible with the continuous phasewithout further surface modification.

One method of assessing the compatibility of the organic nanoparticleswith the liquid continuous phase includes determining whether theresulting composition separates. For transparent liquid continuousphases, one useful method of assessing the compatibility of the organicnanoparticles with the transparent liquid continuous phase includes thestep of combining the organic nanoparticles and the liquid continuousphase and observing whether the organic nanoparticles completelydisperse in the liquid continuous phase. Since the nanoparticles havedimensions smaller than the wavelength of visible light, completedispersion will result in a transparent dispersion.

When the nanoparticles are smaller than the wavelength of visible light,the nanoparticles will appear to form a transparent solution whencompletely dispersed. As the size of the organic nanoparticlesincreases, the haziness of the continuous phase generally increases.Desirable organic nanoparticles are selected such that they do notsettle out of the continuous phase.

A further step in assessing the compatibility of the continuous phaseand the organic nanoparticles includes determining whether, uponsubsequent introduction of liquid to be dispersed in the continuousphase, the composition forms a stable dispersion phase in a usefulperiod of time. A useful period of time may be minutes, hours, days,weeks, or years, depending upon the application. For example, when thedispersion of the invention is a pigment, it is desirable for thedispersion to remain stable for months. However, if the dispersion ofthe invention is a pharmaceutical formulation, it may only be necessaryfor the dispersion to remain stable for several minutes, until thepharmaceutical is administered.

Examples of suitable organic nanoparticles include buckminsterfullerenes(fullerenes), dendrimers, organic polymeric nanospheres, insolublesugars such as lactose, trehalose, glucose or sucrose; aminoacids, andlinear or branched or hyperbranched “star” polymers such as 4, 6, or 8armed polyethylene oxide (available, for example, from Aldrich ChemicalCompany or Shearwater Corporation, Huntsville, Ala.) with a variety ofend groups, and combinations thereof, and include combined materialssuch as a mixture of materials or layers of materials surrounding acentral organic core.

Specific examples of fullerenes include C₆₀, C₇₀, C₈₂, and C₈₄. Specificexamples of dendrimers include polyamidoamine (PAMAM) dendrimers ofGenerations 2 through 10 (G2–10), available from, for example, AldrichChemical Company, Milwaukee, Wis.

Specific examples of a useful organic polymeric nanospheres includenanospheres that comprise polystyrene, available from BangsLaboratories, Inc., Fishers, Ind., as powders or dispersions. Averageparticle sizes of the polystyrene nanospheres range from at least 20 nmto not more than 60 nm. Current commercially available average particlesizes are 20, 30, 50, and 60 nm.

As one skilled in the art will understand, the nanoparticles describedabove may be used as is or surface-modified and in combination.Insoluble nanoparticles (such as sugars, such as trehalose or lactose,or certain dendrimers) should be appropriately surface modified to makethem wettable in the continuous phase. The modification may also be usedto control the volume of the zone of steric exclusion. Non-limitingmethods for surface modification include adsorption, ionic, or covalentchemical reaction with the “surface”, or encapsulating or coating thenanoparticle with a reactive moiety to create a shell that increases the“solubility” of the particle in the continuous phase. If adsorption isthe primary method of modifying the surface of the nanoparticle, theadsorbed species should be selected by one skilled in the art so toavoid substantial desorption and subsequent modification of the surfaceof the medicament.

For surface-modified organic nanoparticles, the nature of the organicparticle component of the surface-modified nanoparticle will prevent thesurface-modified particle from actually dissolving in the continuousphase, i.e., the surface-modified nanoparticles will be dispersed in thecontinuous phase. However, the compatibility of the surface groups withthe continuous phase will give the surface-modified nanoparticles theappearance of dissolving in the continuous phase.

Suitable surface groups can also be selected based upon the solubilityparameter of the surface group and the continuous phase. Desirably thesurface group, or the agent from which the surface group is derived, hasa solubility parameter similar to the solubility parameter of thecontinuous phase. When the continuous phase is hydrophobic, for example,one skilled in the art can select from among various hydrophobic surfacegroups to achieve a surface-modified particle that is compatible withthe hydrophobic continuous phase. Similarly, when the continuous phaseis hydrophilic, one skilled in the art can select from hydrophilicsurface groups, and, when the continuous phase is a hydrofluorocarbon,one skilled in the art can select from among various compatible surfacegroups. The nanoparticle can also include at least two different surfacegroups that combine to provide an organic nanoparticle having asolubility parameter that is similar to the solubility parameter of thecontinuous phase. The surface-modified organic nanoparticles are notamphiphilic.

The surface groups may be selected to provide a statistically averaged,randomly surface-modified particle.

If required, the surface groups are present on the surface of thenanoparticle in an amount sufficient to provide surface-modified organicnanoparticles that are capable of being subsequently dispersed in thecontinuous phase without aggregation. The surface groups desirably arepresent in an amount sufficient to form a monolayer, desirably acontinuous monolayer, on the surface of the nanoparticle.

Surface modifying groups may be derived from surface modifying agents.Schematically, surface modifying agents can be represented by theformula A-B, where the A group is capable of attaching to the surface ofthe particle and the B group is a compatibilizing group (non-reactivewith the continuous phase) or a linking group to a compatibilizinggroup. Compatibilizing groups can be selected to render the particlerelatively more polar, relatively less polar, or relatively non-polar.

PAMAM dendrimers are currently commercially available with primaryamine, hydroxyl, carboxylate sodium salt, mixed amine/hydroxyl, and C₁₂surface functional groups. One skilled in the art will recognize thesedendrimers can be used as is or modified to make the surface compatiblewith the continuous phase if required.

Useful surface-modifying groups for fullerenes and PAMAM dendrimersinclude straight or branched alkyl groups and may range from at least C₃to not greater than C₃₀ and may be any size or range in between C₃ andC₃₀.

Useful organic acid surface-modifying agents include, e.g., oxyacids ofcarbon (e.g., carboxylic acid), sulfur and phosphorus, and combinationsthereof.

Representative examples of polar surface-modifying agents havingcarboxylic acid functionality include CH₃O(CH₂CH₂O)₂CH₂COOH (hereafterMEEAA) and 2-(2-methoxyethoxy)acetic acid having the chemical structureCH₃OCH₂CH₂OCH₂COOH (hereafter MEAA), acid functionalized polyethyleneglycols (PEGS), such as mono(polyethylene glycol) succinate andpolyethylene glycols mono substituted with acetic, propionic, orbutanoic acids. Such polymers or their derivatives may be prepared forexample, as described in U.S. Pat. No. 5,672,662, incorporated herein,or purchased commercially.

Representative examples of non-polar surface-modifying agents havingcarboxylic acid functionality include octanoic acid, dodecanoic acid,and oleic acid.

Examples of suitable phosphorus containing acids include phosphonicacids including, e.g., octylphosphonic acid, laurylphosphonic acid,decylphosphonic acid, dodecylphosphonic acid, octadecylphosphonic acid,and phosphate or phosphonic substituted polyethylene glycols.

Useful organic base surface-modifying agents include, e.g., alkylaminesincluding, e.g., octylamine, decylamine, dodecylamine andoctadecylamine, or amine functionalized polyethylene glycols.

Examples of other useful surface modifying agents include acrylic acid,methacrylic acid, beta-carboxyethyl acrylate,mono-2-(methacryloyloxyethyl)succinate, and combinations thereof. Auseful surface modifying agent that imparts both polar character andreactivity to the nanoparticles ismono(methacryloyloxypolyethyleneglycol)succinatc.

Examples of suitable surface-modifying alcohols include, e.g., aliphaticalcohols including, e.g., octadecyl, dodecyl, lauryl and furfurylalcohol, alicyclic alcohols including, e.g., cyclohexanol, and aromaticalcohols including, e.g., phenol and benzyl alcohol, polyethyleneglycols, monomethyl polyethylene glycols, and combinations thereof.

A variety of methods are available for modifying the surface ofnanoparticles including, e.g., adding a surface modifying agent tonanoparticles (e.g., in the form of a powder or a colloidal dispersion)and allowing the surface modifying agent to react with thenanoparticles. One skilled in the art will recognize that multiplesynthetic sequences to bring the nanoparticle together with thecompatibilizing group are possible and are envisioned within the scope,e.g., the reactive group/linker may be reacted with the nanoparticlefollowed by reaction with the compatibilizing group. Alternatively, thereactive group/linker may be reacted with the compatibilizing groupfollowed by reaction with the nanoparticle. Other useful surfacemodification processes are described in, e.g., U.S. Pat. Nos. 2,801,185and 4,522,958, and incorporated herein.

The nanoparticles, whether surface-modified, or not, have an averageparticle diameter less than about 100 nm; in other embodiments, nogreater than about 50, 40, 30, 20, 15, 10, or 5 nm; in otherembodiments, from about 3 nm to about 50 nm; in other embodiments, fromabout 3 nm to about 20 nm; and in other embodiments, from about 5 nm toabout 10 nm. If the nanoparticles are aggregated, the maximumcross-sectional dimension of the aggregated particle is within any ofthese preferable ranges.

The nanoparticles are employed in the dispersions of the invention in aneffective amount to minimize aggregation of the dispersed particles.Organic nanoparticles are generally present in an amount from 0.005 to0.5 percent by weight and may be present in any amount or range between0.005 and 0.5 percent by weight. In other embodiments, the dispersionsof the invention contain less than 0.5, 0.4, 0.3, or 0.2 percent byweight. One skilled in the art will recognize that the effective amountrequired will depend upon the type of continuous phases, the surfacefunctionality and particle size of the nanoparticles, the dispersedparticle concentration and type, and the presence of other excipients.

The stabilized dispersions of the invention have a liquid continuousphase. The continuous phase may be made up of one or more miscible orsoluble constituents so long as the dispersed particles may be dispersedin all of the constituents of the continuous phase.

Example liquid continuous phases include water, organic liquidsincluding, e.g., acids, alcohols, ketones, aldehydes, amines, amides,esters, glycols, ethers, hydrocarbons, halocarbons, monomers, oligomers,lubricating oils, vegetables oils (including mono- di, andtri-glycerides), silicone oils, moisturizing oils (for example, mineraland jojoba oils), fuel oils, fuels (including kerosene, gasoline, dieselfuel), oligomers of ethylene glycol, alkyl and aryl nitro compounds,partially or fully fluorinated compounds, and polymers and combinationsthereof. In some embodiments, the liquid continuous dispersions may beat least 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20,15, 10, 5 weight percent water and may be any range between 100 and 0weight percent water. In some embodiments, the liquid continuousdispersions may be at least 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45,40, 35, 30, 25, 20, 15, 10, 5 weight percent organic and may be anyrange between 100 and 0 weight percent organic.

The continuous phase may have additional components dissolved in it thatdo not affect the stability of the dispersion (aid or hinder thedispersion of the dispersed insoluble particles), for example,excipients that affect the biologic suitability, salts or organicmaterials, or other beneficial properties of the dispersion.

The dispersed phase may be any particle of interest that have minimalsolubility in the liquid continuous phase. Desirably, the particles havea maximum diameter of less than about 100 micrometers. The dispersedparticles may be inorganic, organic, or a combination thereof. Examplesof dispersed particles include medicaments, carbon black, titaniumdioxide, exfolients, cosmetics, pigments, and abrasives.

Specific medicaments include antiallergics, analgesics, bronchodilators,antihistamines, therapeutic proteins and peptides, antitussives, anginalpreparations, antibiotics, anti-inflammatory preparations, diuretics,hormones, or sulfonamides, such as, for example, a vasoconstrictiveamine, an enzyme, an alkaloid or a steroid, and combinations of thesespecific examples or medicaments which may be employed are:isoproterenol, phenylephrine, phenylpropanolamine, glucagon,adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine,atropine, heparin, morphine, dihydromorphinone, dihydromorphine,ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline,rimiterol, salbutamol, isoprenaline, fenoterol, oxitropium bromide,reproterol, budesonide, flunisolide, ciclesonide, formoterol,fluticasone propionate, salmeterol, procaterol, ipratropiurn,triamcinolone acetonide, tipredane, mometasone furoate, colchicine,pirbuterol, beclomethasone, beclomethasone dipropionate, orciprenaline,fentanyl, diamorphine, and dilitiazem. Others are antibiotics, such asneomycin, cephalosporins, streptomycin, penicillin, procaine penicillin,tetracycline, chlorotetracycline and hydroxytetracycline;adrenocorticotropic hormone and adrenocortical hormones, such ascortisone, hydrocortisone, hydrocortisone acetate and prednisolone;antiallergy compounds such as cromolyn sodium, nedocromil protein andpeptide molecules such as insulin, pentamidine, calcitonin, amiloride,interferon, LHRH analogues, IDNAase, heparin, etc. If applicable, themedicaments exemplified above may be used as either the free base or asone or more salts known to the art. Vaccines may also benefit from thisapproach.

The medicaments exemplified above may be used as either the free base oras one or more salts known to the art. The choice of free base or saltwill be influenced by the physical stability of the medicament in theformulation. For example, it has been shown that the free base ofsalbutamol exhibits a greater dispersion stability than salbutamolsulphate in the formulations of the invention.

The following salts of the medicaments mentioned above may be used:acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide,calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulphate, mucate, napsylate,nitrate, pamoate (embonate), pantothenate, phosphatediphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate,sulphate, tannate, tartrate, and triethiodide.

Cationic salts may also be used. Suitable cationic salts include thealkali metals, e.g., sodium and potassium, and ammonium salts and saltsof amines known in the art to be pharmaceutically acceptable, e.g.,glycine, ethylene diamine, choline, diethanolamine, triethanolamine,octadecylamine, diethylamine, triethylamine,1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol and1-(3,4-dihydroxyphenyl)-2 isopropylaminoethanol.

For pharmaceutical purposes, the particle size of the medicament powdershould desirably be no greater than 100 micrometers diameter. In anotherembodiment, the particle size should be less than 25 micrometers indiameter. Desirably, the particle size of the finely-divided solidpowder should for physiological reasons be less than about 25micrometers and in other embodiments, less than about 10 micrometers indiameter.

Medicinal dispersions according the present invention contain amedicament dispersed in the dispersion in a therapeutically effectiveamount. “Therapeutically effective amount” means an amount sufficient toinduce a therapeutic effect, such as bronchodilation or antiviralactivity. The amount will vary according to factors know to thoseskilled in the art, such as pharmacological activity of the particularmedicament, the condition being treated, the frequency ofadministration, the treatment site, and the presence of any othertherapeutic agents or excipients being co-administered. Theconcentration of medicament depends upon the desired dosage but isgenerally in the range of 0.01 to 15, 0.01 to 10; 0.01 to 5; 0.01 to 4;0.01 to 3; or 0.01 to 2 percent by weight and may be present in anyamount or range between 0.001 and 15 percent by weight.

The medicinal dispersions of the invention may be delivered to thepatient (mammal) by administration means including orally, injection(for example, IV, IP, IM, subQ), topical, through its nasal passage, byinhalation, and combinations thereof. Medicament delivery devices knownto those skilled in the art may be used to administer the pharmaceuticaldispersion. Such devices include for example, pump sprays, nebulizers,syringes, and the like.

Dispersion kits of the invention comprise organic nanoparticles and adispersed phase component. The purpose of such a kit is to allow an enduser of the dispersion to form the dispersion by adding a continuousphase, at a time the end user desires. The kit could containpre-determined amounts of dispersed phase component and organicnanoparticles to be mixed with a suitable amount of a continuous phase.The dispersed phase component and the nanoparticles may be supplied aspowders/particles, or pre-dispersed in a liquid medium. Thenanoparticles and the dispersed phase component may be supplied in thekit mixed together or separately. The kit may also further comprisedirections for use by the end user, for example, amounts, ratios, usefulcontinuous phases, mixing steps, and the like, to form a dispersion ofthe invention.

The dispersions of the invention may also contain surface-modifiedinorganic nanoparticles in combination with organic nanoparticles.Surface-modified inorganic nanoparticles are described in U.S.application Ser. No. 10/449,359, filed on May 30, 2003, incorporatedherein by reference for the description of surface-modified inorganicnanoparticles.

EXAMPLES

Surface Modified PAMAM G-2 Dendrimers (PAMAM G-2) Were Prepared asFollows:

Synthesis of Monofunctional Polyethylene Glycol(MPEG)-N-Hydroxysuccinimide Ester

100 grams (g) munofunctional polyethylene glycol (Polyglykol M, 1100 MW,available from Clariant, Sulzbach am Taunus, Germany, heretoafterreferred to as MPEG 1100) was azeotropically dried in toluene for 24hours followed by the addition of 2 molar excess of sodium metal (4.2 g)with constant stirring at 50° C. The temperature was increased to 75° C.and the reaction was allowed to proceed for the next 24 hours. Thereaction was cooled to room temperature, any unreacted sodium removed,and further cooled to 10° C. t-butyl bromoacetate (30 mL, 2.25 molarexcess, Aldrich Chemical Company) was added and the reaction was allowedto proceed for the next 48 hours with constant stirring, with thetemperature gradually increasing to room temperature. The reaction wasvacuum filtered to remove the NaBr salt, and the toluene was strippedoff on the rotary-evaporator. The MPEG 1100 t-butyl ester product wasdissolved in 300 mL methylene chloride and extracted with purified water(3×400 mL). The organic phase was dried with sodium sulfate, filtered,and the solvent was stripped off on the rotary-evaporator. Any residualvolatiles were stripped by distillation at 110° C. under high vacuum.The product was hydrolyzed at 50° C. for 48 hours with 2.25 g of lithiumhydroxide monohydrate in 175 mL of purified water. The reaction wasacidified to pH3.0 with HCl and extracted with methylene chloride (4×300mL). The organic phase was dried with sodium sulfate, filtered, and thesolvent was stripped off on the rotary-evaporator to yield 12 g of MPEG1100 acid which was dissolved in 150 mL tetrahydrofuran, a 2 molarexcess of 2.6 g N-hydroxysuccinimide (Aldrich Chemical Company) wasadded, along with 2.6 g 1,3-dicyclohexylcarbodiimide (1.1 molar excess,Aldrich Chemical Company). The reaction was allowed to proceed at 0° C.for 24 hours with constant stirring. The resulting mixture was thenvacuum filtered to remove the urea derived from1,3-dicyclohexylcarbodiimide, followed by the removal of the THF on therotary-evaporator.

Acetylated PAMAM G-2 MPEG 1100 Derivative

0.5 g PAMAM G-2 (Aldrich Chemical Company) was dissolved in 100 mLN,N-dimethylformamide at 0° C., and 5.4 g MPEG 1100-N-hydroxysuccinimideester was added. The reaction was allowed to proceed with constantstirring for 2 hours.

Once warmed to room temperature, 100 mL toluene was added. The resultingsolution was rinsed with purified water (5×300 mL) and 1.0 NaOH (5×200mL). The toluene was stripped off on the rotary-evaporator, and theproduct was dried under high vacuum.

In order to cap off any terminal amino groups that had not reacted, theproduct was re-dissolved in 50 mL toluene and treated with excess aceticanhydride. Following 2 hours at 80° C., the solution was cooled slightlyand 50 mL ethanol was added. All solvent was then stripped off on therotary-evaporator, and the acetylated PAMAM G-2-MPEG 1100 derivative wasdried under high vacuum.

Acetylated PAMAM G-2 MPEG 2000 Derivative

PAMAM G-2 MPEG 2000 derivative was prepared according to the sameprocedure used to make the acetylated PAMAM G-2 MPEG 1100 derivativedescribed above except that 0.16 g PAMAM G-2 dendrimer (Aldrich ChemicalCompany) and 1.5 g MPEG 2000 succinimidyl propionate (MPEG-SPA,available from Nektar, San Carlos, Calif.) were used as the startingreagents.

Examples 1–4 Formulations of Albuterol Sulfate Stabilized in Ethanol byAcetylated PAMAM G-2 MPEG 1100 Derivative

Formulations of stabilized dispersions were made by adding the amountsof the following ingredients listed in Table 1 below to a capped vial:the PAMAM G-2 MPEG 1100 derivative (described above), albuterol sulfate,HFA-134a fluorocarbon and 200 proof ethanol.

TABLE 1 Formulations of Albuterol Sulfate Stabilized by PAMAM G-2 MPEG1100 Derivative Acetlyated PAMAM G2 Ethanol MPEG 1100 Albuterol (200Example Derivative Sulfate HFA-134a proof) 1 0.0257 g 0.0385 g 9.9626 g   0 g 2 0.0265 g 0.0393 g 8.9900 g 1.0146 g 3 0.0238 g 0.0396 g 9.9398g    0 g 4 0.0251 g 0.0389 g 8.9585 g 1.0104 gThe sample vials with each formulation were shaken and then allowed tostand. The samples were rated as shown in Table 2 from 1–5 with 1 beingno dispersion (clear solution with flocculated solid) and 5 being atotally dispersed system with uniform opacity. Examples 2 and 4 weregiven a 5 rating. Example 1 was rated a 3 and Example 3 was rated a 4.

TABLE 2 Visual Rating of Suspension Quality of Albuterol SulfateSuspensions Stabilized by PAMAM G-2 MPEG 1100 Derivative Visual Ratingof Suspension Quality Description of Suspension 1 Agglomerates formedduring shaking 2 Flocculation began immediately after shaking ceased 3Flocculation began 1–5 seconds after shaking ceased 4 Flocculation began5–30 seconds after shaking ceased 5 Flocculation began more than 30seconds after shaking ceased

Examples 5–6 Comparative Example A Beclomethasone DipropionateDispersions in Water Stabilized by Acetylated PAMAM G-2 MPEG1100Derivative

Formulations of stabilized dispersions were made by adding the amountsof the following ingredients listed in Table 3 below to a capped vial:the acetylated PAMAM G-2 MPEG110 dendrimer derivative described above,beclomethasone dipropionate, and ultrapure (18 MΩ)water.

TABLE 3 Acetylated PAMAM G-2 MPEG 1100 Beclomethasone Example DerivativeDipopionate Ultrapure Water 5 0.0260 g 0.0262 g 10.0087 g 6 0.0103 g0.0267 g 10.0058 g Comparative    0 g 0.0255 g 10.0245 g Example A

The sample vials with the formulations in Table 3 were shaken for about30 seconds and then were allowed to stand undisturbed for 20 minutes.The suspension characteristics were observed. Comparative Example A hadvery little medicament dispersed within the liquid. The majority of themedicament particles remained on the surface of the liquid or on thewalls of the vial above the liquid surface. Examples 5 and 6 hadnoticeably more medicament dispersed in the liquid and less medicamentvisible on the surface of the liquid or on the walls of the vial.Example 5 appeared to have more medicament dispersed in the liquid andless durg on the surface of the liquid and walls of the vial than didExample 6.

Examples 7 and 8 and Comparative Examples B and C Stabilization ofDispersions of Budesonide and Fluticasone in Water using PAMAM G-2 MPEG2000 Derivative

Formulations of dispersions were made by adding the amounts of theingredients listed in Table 4 to a capped vial.

TABLE 4 Formulations of Budesonide and Fluticasone Propionate in WaterWith PAMAM G-2 MPEG 2000 Derivative as Stabilizer Acetylated PAMAMUltrapure G-2 MEG Fluticasone (18 MΩ) Example 2000 Derivative BudesonidePropionate Water 7 0.0052 g 0.0159 g 0.0000 g 5.0231 g Comparative0.0000 g 0.0180 g 0.0000 g 5.0256 g Example B 8 0.0053 g 0.0000 g 0.0122g 5.0000 g Comparative 0.0000 g 0.0000 g 0.0144 g 5.0742 g Example C

Each vial was shaken for 30 seconds. The vials were then leftundisturbed for 20 minutes. After 20 minutes, the suspensioncharacteristics of the vials were observed and recorded. ComparativeExample B and Example 7 appeared uniformly dispersed initially aftershaking. After 20 minutes, Comparative Example B had settled slightly,whereas Example 7 remained unchanged (no settling observed). Initiallyafter shaking Comparative Example C and Example 8 appeared uniformlydispersed. After 20 minutes, the solid particulates in ComparativeExample C had settled out whereas the solid particulates in Example 8were still uniformly dispersed and indistinguishable from theirappearance immediately after shaking.

Example 9 Stabilization of Dispersions of Carbon Black with PolystyreneNanospheres

0.02 g 20 nm polystyrene nanospheres (Bang Laboratories, Inc., Fishers,Ind.) and 0.05 g carbon black were added to a capped small vialcontaining 0.93 g water. The vial was shaken by hand for 30 seconds. Thevial was allowed to stand. After standing for 5 minutes, the dispersionwas observed to be stable.

Examples 10 and 11 Stabilization of Carbon Black and Alumina withOctyl-Substituted C₆₀(octyl-C₆₀)

0.02 g octyl-C₆₀, 0.05 g carbon black, and 0.93 g toluene were added toa capped small vial. The vial was shaken by hand for 30 seconds. Afterstanding for 5 minutes the dispersion was observed to be stable. Asecond vial was charged with 0.02 g octyl-C₆₀, 0.05 g alumina, and 0.93g toluene. After shaking and standing for 5 minutes, this dispersion wasalso observed to be stable.

All patents, patent applications, and publications cited herein are eachincorporated by reference, as if individually incorporated. Foreseeablemodifications and alterations of this invention will be apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. This invention should not be restricted to theembodiments that are set forth in this application for illustrativepurposes.

1. A stable dispersion comprising: a continuous phase comprising acontinuous liquid phase and a plurality of organic nanoparticles,wherein the nanoparticles are selected from the group consisting ofbranched or hyperbranched polyethylene oxide; and combinations thereof;and a dispersed phase comprising particles dispersed in the continuousphase.
 2. The dispersion of claim 1 wherein the nanoparticles aresurface-modified with polyethylene glycols or alkyl groups.
 3. Thedispersion of claim 2 wherein the alkyl groups are at least C₃.
 4. Thedispersion of claim 2 wherein the alkyl groups are not greater than C₃₀.5. The dispersion of claim 2 wherein the alkyl groups range from C₃ toC₂₂.
 6. The dispersion of claim 2 wherein the alkyl groups range from C₃to C₁₈.
 7. The dispersion of claim 2 wherein the alkyl groups range fromC₃ to C₁₂.
 8. The dispersion of claim 2 wherein the alkyl groups are C₃to C₈ and any combination or integer therebetween.
 9. The dispersion ofclaim 1 wherein the branched or hyperbranched polyethylene oxidenanoparticles comprise 4, 6, or 8 armed polyethylene oxide, orcombinations thereof.
 10. The dispersion of claim 1 wherein thecontinuous phase comprises an organic liquid.
 11. The dispersion ofclaim 1 wherein said individual nanoparticles have a particle diameterno greater than about 50 nanometers.
 12. The dispersion of claim 1wherein said individual nanoparticles have a particle diameter in therange of from about 3 nanometers to about 50 nanometers.
 13. Thedispersion of claim 1 wherein said individual nanoparticles have aparticle diameter of no greater than about 20 nanometers.
 14. Thedispersion of claim 1 wherein said individual nanoparticles have aparticle diameter in the range of from about 3 nanometers to about 20nanometers.
 15. The dispersion of claim 1 wherein said individualnanoparticles have a particle diameter in the range of from about 3nanometers to about 10 nanometers.
 16. The dispersion of claim 1 whereinthe dispersion comprises less than 0.001 percent by weight ofsurfactant, surface-active agents, detergents, and conventionaldispersants.
 17. The dispersion of claim 1 wherein the liquid continuousphase is selected from the group consisting of water, organic acids,alcohols, ketones, aldehydes, amines, amides, esters, glycols, ethers,hydrocarbons, halocarbons, monomers, oligomers, lubricating oils,vegetable oils, silicone oils, mineral and jojoba oils, fuel oils,kerosene, gasoline, diesel fuel, oligomers of ethylene glycol, alkyl andaryl nitro compounds, partially or fully fluorinated compounds, andcombinations thereof.
 18. The dispersion of claim 1 further comprisingsurface-modified inorganic nanoparticles.
 19. A method of stabilizing adispersion comprising adding an effective amount of organicnanoparticles to a dispersion comprising a dispersed solid phase and aliquid continuous phase, wherein the nanoparticles are selected from thegroup consisting of branched or hyperbranched polyethylene oxide; andcombinations thereof.
 20. A dispersion kit comprising a dispersed phasecomponent to be dispersed in a continuous phase and organicnanoparticles selected from the group consisting of branched orhyperbranched polyethylene oxide and combinations thereof.
 21. A stabledispersion comprising: a continuous phase comprising a continuous liquidphase and a plurality of organic nanoparticles that comprisepolystyrene; and a dispersed phase comprising particles dispersed in thecontinuous phase wherein the particles are carbon black, titaniumdioxide, pigments, abrasives, exfolients, or cosmetics.
 22. A stabledispersion comprising: a continuous phase comprising a continuous liquidphase and a plurality of organic nanoparticles having an averageparticle diameter of less than 100 nanometers, wherein the nanoparticlesare selected from the group consisting of amino acids, insoluble sugarsand combinations thereof.
 23. A method of stabilizing a dispersioncomprising adding an effective amount of organic nanoparticles having anaverage particle diameter of less than 100 nanometers to a dispersioncomprising a dispersed solid phase and a liquid continuous phase,wherein the nanoparticles are selected from the group consisting ofinsoluble sugars, amino acids and combinations thereof.
 24. A dispersionkit comprising a dispersed phase component to be dispersed in acontinuous phase and organic nanoparticles having an average particlediameter of less than 100 nanometers selected from the group consistingof insoluble sugars, amino acids, and combinations thereof.